Process for the reduction of a phenolic ether to its dihydro derivative



United States Patent PROCESS FOR THE REDUCTHG'N DE A PHENOLHC ETHER TOITS DEHYDRO DEREVATIVE Alfred L. Wilde, Madison, Wis, and Norman A.Nelson,

Kalamazoo, Mich assignors to Wisconsin Alumni Re= search Foundation,Madison, Win, a corporation of Wisconsin No Drawing. Continuation ofapplication Ser. No. 392,734, Nov. 17, 1953. This application Oct. 2,19611, Ser. No. 141,986

6 Claims. (Cl. 260-3975) The present invention relates to a chemicalprocess and more particularly to an improved process of converting alkylaryl ethers to dihydro enol ethers. These latter compounds are suitablefor cleavage to [3;yor cap-unsaturated ketones and are of particularinterest in the steroid hormone field.

The reduction of a phenolic ether to its dihydro derivative, by theaction of sodium and ethanol in liquid ammonia was first described byWooster for anisole. Wooster, US. Patent No. 2,182,242. Durin the pastyears this reaction has been clarified, improved, and utilizedextensively by Birch. Birch, A. 1., Quart. Rev., 4, 69 (1950). Under theBirch procedure, the metal, sodium, is added last to thealcoholic-liquid ammonia-phenolic ether reaction mixture. This procedureemploying ethanol, liquid ammonia, and sodium proved in practice (1) towork satisfactorily for easily reducible phenolic ethers, (2) to give atbest only poor yields with phenolic ethers which are not easilyreducible, i.e., phenolic ethers of the only fairly readily andmoderately difiicult reducible types, and (3) to give substantially noneof the desired dihydro products with phenolic ethers of the difiicultlyreducible type. Examples of alkyl aryl ethers falling within thesegeneral classes are: anisole and 2-methoxy-5,6,7,8-tetrahydronaphthalenewhich are typical of easily reducible compounds; estradiol 3 methylether which is a fairly readily reducible compound; 4-cyclohexylanisoleand 4- cyclohexylphenoxyethanol which are moderately diflicult toreduce; 1-methoxy-5,6,7,8-tetrahydronaphthalene which is difiicult toreduce, and dlm-3-(p-methoxyphenyD-4- (4'-hydroxycyclohexyl)-hexanewhich is an unusually diificult compound to reduce. With the diflicultlyreducible 1-methoxy-5,6,7,S-tetrahydronaphthalene (as distinguished fromthe easily reducible 2-methoxy isomer) Birch reported, for example, thathis process gave only a trace of the desired reduction product. Birch,A. 1., J. Chem. Soc., 430 (1944).

In our experiments, the application of Birchs conditions to4-cyclohexylanisole, i.e., addition of sodium metal to a mixture ofliquid ammonia, ethanol and phenolic ether, also gave little or noreduction, 95% of the starting ether being recovered.

In attempts to overcome the problems encountered with the non-easilyreducible alkyl aryl or phenolic ethers various modifications have beentried. An example of one modification was the use of potassium in placeof sodium in the Birch process. This, however, showed little improvementover the use of sodium. With 4-cyclohexylanisole the use of ether,beneficial in other cases of com pounds insoluble in ammonia at 33 C.,and replacement of ethanol by methanol or the slower reacting isopropylalcohol were also all tried but failed to give re duction. Indeed, thelatter modification applied to 4- methoxybiphenyl gave some reduction ofthe non-oxygenated ring affording some unwanted 4-cyclohexylanisole insmall yield. With estradiol and hexestrol Birch also found it necessarywith his process to prepare derivatives mole soluble in ammonia, such asthe mono ethers of ethylene glycol and glycerol, in order to obtainreduction even in moderate yields. Birch, A. 1., and Mukherji, S.

M., J. Chem. Soc., 2531 (1949). Aside from the relatively unsatisfactoryyields, this modification possesses the disadvantage of requiring thepreparation of special derivatives in place of the less expensive ormore readily available methyl derivatives.

In our investigations with the Birch process we tried the hydroxyethylether of 4-cyclohexylphenol and obtained some reduction to the desiredenol ether, the crude dinitrophenylhydrazone of the unsaturated ketonebeing isolated in 16% yield after hydrolysis of the enol ether withsulfuric acid. The hydroxyethyl ether of 4-hydroxybiphenyl was alsosubjected to reduction under the Birch conditions but none of thedesired enol ether could be isolated. Interestingly enough, thisreaction mixture was found to contain some cyclohexylbenzene, thehydroxyethoxy group having been eliminated during reduction of theoxygenated ring. During our investigations we also tried adding theethanol last to the blue solution of sodium and 4-cyclohexylanisole in amixture of liquid ammonia and ether. This modification proved of specialinterest as the reduction to the desired enol ether proceeded to anappreciable extent, 35% of the dinitrophenylhydrazone of the unsaturatedketone being isolated. This result was especially unexpected as Birchhas implied that it was necessary for the alcohol to be presentinitially in excess, to avoid demethylation. With continued research wethen discovered that 4-cyclohexylanisole could be converted to thedesired 2,5-dihydro-4-cyclohexylanisole in yields of 84-90%, providingthe alcohol was added last and lithium was substituted for sodium. Thefollowing general procedure and examples will serve to illustrate ourinvention.

GENERAL PROCEDURE A solution of the alkyl aryl or phenolic ether to bereduced is first made in a mixture of liquid ammonia and a dry, inert,organic cosolvent such as diethyl ether or 1,2-dimethoxyethane. This canbe conveniently done by dissolving the phenolic ether in the cosolventand then adding liquid ammonia with stirring. To the resultinghomogeneous solution is next added lithium, e.g., in wire form, in smallpieces, e.g., over a period of about 110 minutes, depending on thequantity of metal. After stirring the resulting blue solution for ashort time, e.g., about ten minutes, alcohol, e.g., absolute ethanol, isthen slowly added, e.g., dropwise over a period of about fifteen tothirty minutes. As there may be a tendency for foaming to occur near theend of this addition, the use of a reaction flask filled to only /3 upto /2 its capacity is preferred. When the blue color has disappeared thereaction mixture can be worked up in various ways known in the art forrecovery of the dihydro product. One of the preferred procedures is toremove the ammonia by evaporation, add ether and water, separate thelayers and extract the aqueous layer with ether. The combined organicextracts are then washed, e.g., with saturated salt solution, dried,e.g., over potassium carbonate, sodium sulfate or the like, the etherremoved and the desired dihydro or enol other product isolated from theresidue by crystallization or distillation as appropriate.

Example I 2,5-DIHYDRO-4-CYCLOHEXYLANISOLE A solution of 4.0 g. of4-cyclohexylanisole in 200 ml. ether was reduced according to thegeneral procedure described above using 250 ml. liquid ammonia, 4.2 g.lithium wire and 37 g. absolute ethanol. Crystallization of the productfrom dilute ethanol gave the colorless dihydro derivative, M.P. 65-66 in84-89% yield containing less than 1% unreduced material. Furtherrecrystallization from alcohol raised the melting point to 65 .466.2.

a; 9 SODIUM REDUCTIONS OF -l-CYCLOI-IEXYLANISOLE The replacement oflithium by an equivalent amount of sodium in the above procedure gaveincomplete reduction; hydrolysis of the enol ether with sulfuric acidand conversion of the enol ether to the dinitrophenylhydrazone of4-cyclohexyl-3-cyclohexenone indicated 35% reduction. In a variety ofruns using ether, methylamine or no cosolvent with the liquid ammonia,employing ethanol or 2-propanol and adding the metal (sodium orpotassium) last according to the general procedure of Birch, noreduction occurred, as evidenced by recovery of the starting materialand failure to obtain any dinitrophenylhydrazone from the material afterthe reduction treatment.

When the reduction was carried out in the same way except adding thealcohol to the ammonia-ether solution and adding the lithium last over aten-minute period, 76% of the dihydro compound, M.P. 64-65.5, wasobtained. This crude material, however, contained 4% of startingmaterial on the basis of ultraviolet absorption.

Example 11 REDUCTION OF 4-CYCLOHEXYLPHENOXYETHANOL Treatment of 4.4 g.of this hydroxyethyl ether in 100 ml. of diethyl ether and 150 ml.liquid ammonia with 2.1 g. of lithium and 18.5 g. ethanol in accordancewith the general procedure described above resulted in 62% of crudeproduct, M.P. 46-48. The conversion of this product to thedinitrophenylhydrazone of 4-cyclohexyl-2- cyclohexenone, M.P. 112-116",in 68% yield, together with the crude derivative from the oily filtrate,indicated a maximum of 46% reduction with this derivative. Using thegeneral procedure of Birch, except with 2-propanol and ether ascosolvent and adding the sodium last, the extent of reduction wasestimated to be 16%, based on the crude dinitrophenylhydrazone, M.P.115-120".

Example Ill REDUCTION OF l-METHOXY-f),6,7,8-TETRAHYDRO- NAPHTHALENE Asolution of 20 g. of the methyl ether in 100 ml. 1,2- dimethoxyethane(dried over potassium hydroxide and distilled from sodium) and 400 ml.ammonia was reduced by the general procedure given above, using 6.4 g.of lithium wire, stirring for ten minutes and adding g. absolute ethanol(or 60 g. isopropyl alcohol) over a fifteen to twenty-five-minuteperiod. Distillation of the isolated product gave a crude mixture, B.P.95-l31 (20 mm.) in 83-87% yield. From the absorption maximum at 278 mthis material contained 8-2l% of unreduced material in the various runs.Conversion to the dinitrophenylhydrazone of the conjugated ketone gavethis derivative, M.P. 268 dec., in -5 8% over-all yields from1-methoxytetrahydronaphthalene.

Example IV 1,4-DII-IYDRO-3JTfl-ESTRADIOL 3-l\IETHYL ETHER The reductionwas carried out by the general procedure described above. To a solutionof 1.38 g. of 3,17B-estradiol 3-methyl ether (M.P. 118-119) in 110 ml.anhydrous ether was added 140 ml. liquid ammonia followed by 1.4 g.lithium wire in small pieces. Ten minutes later 16 ml. of absoluteethanol was added dropwise over a l0-20-minute period. After removingmost of the ammonia and carefully adding cold water, the product wasextracted with ether, washed with Claisens alkali (cf. Claisen et al.,Ann. 418, 96 (1919)), water, saturated salt solution and dried oversodium sulfate. Crystallization of the product from 6 ml. absolutealcohol and 25 ml. petroleum ether (B.P. -68") gave the desired productwith a M.P. 118-119.5 in 90% yield. In other runs the yields ran about86-99%, the lower yield resulting from the use of 1,2-di-methoxyethaneinstead of ether.

in a run carried out employing sodium in accordance t with the generalprocedure of Birch, except for the use of ether and isopropyl alcohol ascosolvents, a solid product, M.P. 97-l07, was obtained in 84% yield. Anexamination of this crude product by ultraviolet spectrum, however,showed it to contain as much as 28% unreduced estradiol B-methyl ether.

Example V REDUCTION OF 3-(p-METHOXYPIIENYL)-4-(-t-HYDROX-YCYCLOHEKYL)-HEXANE (HEXAHYDROHEXESTROL MONOMETIIYL ETHER) To 600 mg. ofhexahydrohexestrol isomer B (M.P. l32.5-l34) in 10 ml. methanol and 0.8g. potassium hydroxide in 10 ml. water were added concurrently overthirty minutes and with stirring at 30-35 3 ml. dimethyl sulfate and 2g. potassium hydroxide in 5 ml. water. After another thirty minutesammonia was added, the product was extracted with three portions ofether, the latter washed with Claisens alkali, water and dried. Afterevaporation of the ether, the oil was dried to constant weight at 50 and0.05 mm. In some runs the oil crystallized, micro M.P. 44-53", but wasused without purification.

To the oily methyl ether as prepared above (600 mg.) dissolved in 60 ml.1,2-dimethoxyethane (dried over potassium hydroxide and distilled fromsodium) was added ml. liquid ammonia and 0.6 g. (44 equivalents permole) lithium wire in portions. After fifteen minutes stirring enoughabsolute ethanol (5 ml.) was added (dropwise over 15 minutes) to justdischarge the blue color, 15 ml. ammonia and 0.4 g. (29 equivalents permole) lithium were added and after another ten minutes 3.5 m1. absolutealcohol was added over a ten-minute period. Finally the ammonia wasevaporated, ether and cold water added and the product isolated asdescribed above. The desired product was obtained as a neutral oil in ayield of 97%.

The critical features of the invention as illustrated above are (1) thereaction of lithium with an alkyl aryl ether in solution in a mixture ofliquid ammonia and an inert cosolvent and (2) followed by the additionof the alcohol. The order in which the reactants are added can be variedas long as the alcohol is added last to the lithium-alkyl arylether-liquid ammoniacosolvent reaction mixture. Optimum conditions forparticular reductions may vary but can be readily ascertained bypreliminary test. As illustrated in Example V, the process can berepeated by adding to the initial reaction mixture an additional amountof lithium followed by an additional amount of alcohol, etc. Any inertorganic cosolvent or mixtures thereof can be employed in the process aslong as they are liquid at the reaction temperature (-33) and increasethe solubility of the alkyl aryl ether in the liquid ammonia solution oflithium. Diethyl ether and 1,2-dimethoxyethane are two of the preferredtypes, the optimum cosolvent for any particular reaction also beingreadily ascertainable by preliminary test. The alcohols employed can beany of the lower aliphatic alcohols (lower alkanols) such as methanol,n-propanol, isopropanol, etc., or mixtures of the same, although thereadily available ethanol is one of the preferred. Alcohols such astertiary butyl alcohol can also be employed although their use isordinarily not preferred due to the increased tendency toward foamingduring the reaction with the use of the larger molecule alcohols. Thealkyl group of the alkyl aryl others can be any of the lower alkylgroups such as ethyl, propyl, butyl, amyl, Lexy], etc., although the useof lower alkoxy groups containing 1 to 6 carbon atoms or less andparticularly the readily available methyl (methoxy) aryl ether compoundsare preferred. The alkyl group of the alkoxy group as shown above (e.g.,Example II) can also contain a hydroxy group or groups.

The reduction takes place in the oxygenated (lower allroxy phenyl or sixcarbon) ring of the aryl group to produce an enol ether or dihydrocompound. In other words, one of the three double bonds in theoxygenated six carbon ring is reduced to provide an oxygenated ringcontaining only two double bonds. These latter compounds as noted aboveare suitable for cleavage to unsaturated ketones useful in the synthesisof physiologically active compounds.

The i-mproved process of the present invention can be employed toadvantage to reduce alkyl aryl ethers and has given markedly superioryields with alkyl aryl ether compounds which are not of the easilyreducible type. With the easily reducible compounds the process of theinvention gives at least as good yields as the Birch process ormodifications thereof known heretofore.

The process of the present invention can be used to advantage to reducethe lower alkoxy substituted aromatic ring of any polycyclic aromaticcompound including hydroaromatic polycyclic compounds containing atleast one lower alkoxy substituted aromatic ring. All

references to melting and boiling points herein are given in C.

This application is a continuation of our copending application SerialNo. 392,734, filed November 17, 1953, now abandoned.

We claim:

1. The improved process of reducing a R-aryl ether, where R is selectedfrom the group consisting of lower alkyl and hydroxy lower alkyl groups,to the corresponding dihydro enol ether compound which comprisesreacting the aryl ether with lithium in a mixture consisting of liquidammonia and an inert organic solvent by stirring the mixture for a shorttime, slowing adding a lower alkanol dropwise to the resulting bluereaction mixture and then recovering the dihydro product from thereaction mixture.

2. The process of claim 1, where the organic solvent is ether and thealkanol is ethanol.

3. The process of claim 1 where the organic solvent is1,2-dimethoxyethane and the alkanol is ethanol.

4. The process of claim 1 where the alkyl aryl ether is a methyl arylether.

5. The process of converting a six carbon aromatic ring having .a loweralkoxy group attached thereto, to the corresponding dihydro ringcompound which comprises reacting said ring with lithium in a mixtureconsisting of liquid ammonia and an inert organic solvent by stirringthe mixture for about ten minutes and then adding a lower alkanoldropwise over a period of about fifteen to thirty minutes :to theresulting blue reaction mixture.

6. Tthe process of preparing 1,4-dihydro-3,17p-estradiol 3-methyl etherwhich comprises reacting 3,17,6- estradiol 3-methyl ether with lithiumin a mixture consisting of liquid ammonia and an inert organic solventby stirring the mixture for about ten minutes and then adding a loweralkanol dropwise over a ten to twenty minute period to the resultingreaction mixture.

References Cited in the file of this patent UNITED STATES PATENTS

1. THE IMPROVED PROCESS OF REDUCING A R-ARYL ETHER, WHERE R IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL AND HYDROXY LOWER ALKYL GROUPS, TO THE CORRESPONDING DIHYDRO ENOL ETHER COMPOUND WHICH COMPRISES REACTING THE ARYL ETHER WITH LITHIUM IN A MIXTURE CONSISTING OF LIQUID AMMONIA AND AN INERT ORGANIC SOLVENT BY STIRRING THE MIXTURE FOR A SHORT TIME, SLOWING ADDING A LOWER ALKANOL DROPWISE TO THE RESULTING BLUE REACTION MIXTURE AND THEN RECOVERING THE DIHYDRO PRODUCT FROM THE REACTION MIXTURE.
 6. THE PROCESS OF PREPARING 1,4-DIHYDRO-3, 17B-ESTRADIOL 3-METHYL ETHER WHICH COMPRISES REACTING 3,17BESTRADIOL 3-METHYL ETHER LITHIUM IN A MIXTURE CONSISTING OF LIQUID AMMONIA AND AN INERT ORGANIC SOLVENT BY STIRRING THE MIXTURE FOR ABOUT TEN MINUTES AND THEN ADDING A LOWER ALKANOL DROPWISE OVER A TEN TO TWENTY MINUTE PERIOD TO THE RESULTING REACTION MIXTURE. 